Degree Of Immune Response Research Articles

DNA vaccine dual-expressing viral hemorrhagic septicemia virus glycoprotein and C-C motif chemokine ligand 19 induces the expression of immune-related genes in zebrafish (Danio rerio).

Glycoprotein (G protein)-based DNA vaccines are effective in protecting aquaculture fish from rhabdoviruses but the degree of immune response they elicit depends on plasmid concentration and antigen cassette. Here, we developed a DNA vaccine using the viral hemorrhagic septicemia virus G (VG) gene and chemokine (C-C motif) ligand 19 (CCL19)a.2 regulated by the CMV promoter as the molecular adjuvant. After transfection of the prepared plasmid (pVG + CCL19) into epithelioma papulosum cyprini cells, mRNA expression was confirmed through quantitative real-time polymerase chain reaction. The vaccine was intramuscularly injected into zebrafish (Danio rerio), and 28 days after immunization, viral hemorrhagic septicemia virus (105 TCID50/10 µl/fish) was intraperitoneally injected. A survival rate of 68% was observed in the pVG + CCL19 group but this was not significantly different from the survival rate of fish treated with pVG alone, that is, without the adjuvant. However, the expression of interferon- and cytokine-related genes in the spleen and kidney tissues of zebrafish was significantly increased (p < 0.05) on days 1, 3, 7, and 14 after immunization. Thus, CCL19a.2 induced an initial immune response as a molecular adjuvant, which may provide initial protection against virus infection before vaccination-induced antibody formation. This study provides insights on the functions of CCL19a.2 adjuvant in DNA vaccines.

Changes in T lymphocyte subsets in different tumors before and after radiotherapy: A meta-analysis.

2525 Background: Radiation therapy (RT) induces an immune response, but the relationship of this response with tumor type is not fully understood. Methods: We searched English-language electronic databases including PubMed, EMBASE, and the Cochrane Library to collect studies about the changes in CD3+ T lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes before and after radiotherapy in tumor patients from January 2015 to December 2019. The quality of the included literature was evaluated using the NOS scale provided by the Cochrane Collaboration, and statistical software RevMan 5.4 was used to analyze the included literature. p &lt; 0.05 was considered to indicate statistical significance. Results: A total of 17 studies in 15 articles involving 1735 tumor patients were included. All data were collected within 1 month before or after radiotherapy. Meta-analysis showed that numbers of CD3+ T lymphocytes were significantly reduced after radiotherapy compared with before treatment (standard mean difference [SMD]: -0.76; 95% CI [-1.46, -0.06]; p = 0.03), as were those of CD4+ T lymphocytes (SMD: -0.50; 95% CI: [-0.88, -0.12]; p = 0.01), but there was no statistically significant difference for CD8+ T lymphocytes (SMD: 0.19; 95% CI: [-0.23, 0.62]; p = 0.38). Subgroup analysis showed significant decreases in CD3+ T lymphocytes in liver cancer,esophageal cancer, head and neck cancer, pancreatic cancer and breast cancer after radiotherapy. Numbers of CD4+T lymphocytes increased after radiotherapy in breast cancer,and a decrease was observed in liver cancer, esophageal cancer, colorectal cancer, and head and neck cancer. CD8+ T lymphocyte numbers also increased compared with before radiotherapy in esophageal cancer, lung cancer, and colorectal cancer. But a decrease in liver cancer and head and neck cancer. Conclusions: Numbers of CD3+ and CD4+ T lymphocytes decreased after radiotherapy, whereas CD8+ T lymphocytes showed no significant change. Within 1 month of radiotherapy, the tumor microenvironment showed an immunosuppressive state. The degree of immune response induced by radiotherapy differed between tumor types.

Vascularized Muscle Flap to Reduce Wound Breakdown During Flexible Electrode-Mediated Functional Electrical Stimulation After Peripheral Nerve Injury.

The success of devices delivering functional electrical stimulation (FES) has been hindered by complications related to implants including skin breakdown and subsequent wound dehiscence. Our hypothesis was that a vascularized muscle flap along the dorsal surface of an epimysial electrode would prevent skin breakdown during FES therapy to treat atrophy of the gastrocnemius muscle during peripheral nerve injury. Resection of a tibial nerve segment with subsequent electrode implantation on the dorsal surfaces of the gastrocnemius muscle was performed on ten Lewis rats. In five rats, the biceps femoris (BF) muscle was dissected and placed along the dorsal surface of the electrode (Flap group). The other five animals did not undergo flap placement (No Flap group). All animals were treated with daily FES therapy for 2 weeks and degree of immune response and skin breakdown were evaluated. The postoperative course of one animal in the No Flap group was complicated by complete wound dehiscence requiring euthanasia of the animal on postoperative day 4. The remaining 4 No Flap animals showed evidence of ulceration at the implant by postoperative day 7. The 5 animals in the Flap group did not have ulcerative lesions. Excised tissue at postoperative day 14 examined by histology and in vivo Imaging System (IVIS) showed decreased implant-induced inflammation in the Flap group. Expression of specific markers for local foreign body response were also decreased in the Flap group.

Abstract A001: Phase I study of vaccine therapy with a cocktail of peptides for pediatric patients with refractory solid tumors

Abstract Recently, the aggressive intervention of multidisciplinary therapy has resulted in improving the life prognosis of pediatric solid tumors. However, in the pediatric patients with metastatic or refractory solid tumors, the prognosis remains poor. Additionally, various critical, late complications could continue to occur. Therefore, the development of novel, effective therapy is urgently required. Immunotherapy could be the one of effective therapeutic strategy for pediatric solid tumors. Actually, the KOC1, FOXM1, and KIF20A might be capable of being an ideal target of anticancer immunotherapy against pediatric solid tumors that highly had expression of these cancer antigens. In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of NCCV cocktail 1 vaccine, a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric solid tumors. Experimental Design: Twelve patients with refractory pediatric solid tumors, including 3 patients with neuroblastoma, 2 patients with Ewing’s sarcoma, 5 patients with rhabdomyosarcoma, and 2 patients with osteosarcoma, underwent NCCV cocktail 1 vaccination (intradermal injections every a week). In 9 enrolled patients, the histologic expression of KOC1, FOXM1, and KIF20A before vaccination were evaluated using tissue specimen obtained from biopsy or surgery. The primary endpoint was the safety of NCCV cocktail 1 vaccination. The secondary endpoints were immune response, as measured by in vivo and in vitro interferon (IFN)-r enzyme-linked immunospot (ELISPOT) assay and Dextramer assay, and the clinical outcomes of tumor response and progression free survival (PFS).Results:No dose-limiting toxicity (DLT) was observed in this trial, and we suggested that NCCV cocktail 1 vaccination was well-tolerated. Of nine patients, 6 patients (66.7%), 6 patients (66.7%), and 7 patients (77.8%), exhibited positive expression of KOC1, FOXM1, and KIF20A before vaccination, respectively. Of eleven patients, 4 patients (36.4%), 8 patients (72.7%), and 5 patients (45.5%) were induced peptide-specific CTL response of KOC, FOXM1, and KIF20A by NCCV cocktail 1 vaccine, respectively. Also, 4 patients showed stable disease after 8 weeks, and 2 patients showed during of remission for more than 11 months after second complete remission. Additionally, patients with high peptide-specific CTL frequencies of all KOC, FOXM1, and KIF20A (n=4) had better PFS than those with low frequencies (n=7) by Kaplan-Meier analysis (log-rank test, P =0.019). By Cox proportional hazard models, univariate and multivariate analysis indicated that only induction of peptide specific CTL in all of these three antigens was independent factor related to PFS (P = 0.039; HR = 5.60; 95% CI 1.09-28.91, P = 0.050; HR = 6.00; 95% CI 1.00-36.32, respectively). Conclusions:The results of this trial demonstrated that the NCCV cocktail 1 vaccine was safe and had ability to induce some degree of immune response, which could result in the benefit for preventing the recurrence of pediatric solid tumors, especially after a second complete remission. Citation Format: Yu Akazawa, Ako Hosono, Toshiaki Yoshikawa, Hide Kaneda, Junichi Hara, Yoshiaki Kinoshita, Kenichi Kohashi, Atsushi Manabe, Yoko Shioda, Kayoko Shoda, Manami Shimomura, Shoichi Mizuno, Yasunari Nakamoto, Tetsuya Nakatsura. Phase I study of vaccine therapy with a cocktail of peptides for pediatric patients with refractory solid tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A001.

Genetic diversity confers colony-level benefits due to individual immunity.

Several costs and benefits arise as a consequence of eusociality and group-living. With increasing group size, spread of disease among nest-mates poses selective pressure on both individual immunity and group-level mechanisms of disease resistance (social immunity). Another factor known to influence colony-level expression of disease is intracolony genetic diversity, which in honeybees (Apis mellifera) is a direct function of the number of mates of the queen. Colonies headed by queens with higher mating numbers have less variable infections of decreased intensity, though the underlying mechanisms remain unclear. By pathogen-challenging larvae in vitro, we decoupled larval immune response from mechanisms of social immunity. Our results show that baseline immunity and degree of immune response do not vary with genetic diversity. However, intracolony variance in antimicrobial peptide production after pathogen challenge decreases with increasing genetic diversity. This reduction in variability of the larval immune response could drive the mitigation of disease observed in genetically diverse colonies.

Oligodendrocytes engineered with migratory proteins as effective graft source for cell transplantation in multiple sclerosis.

Multiple sclerosis (MS) is characterized by widespread immunomodulatory demyelination of the CNS resulting in nerve cell dysfunction. Accordingly, treatment strategies have been centered on immunodulation and remyelination, with the former primarily focused on reducing the pathology rather than enhancing myelin repair which the latter targets. While conceding to the emerging view of heterogeneity in the pathology of MS, which precludes variations in degree of immune response (i.e., inflammation) and demyelination, the concept of enhancing myelin repair is appealing since it is likely to provide both disease-reducing and disease-inhibiting therapeutic approach to MS. In this regard, we and several others, have proposed that cell replacement therapy is an effective strategy to repair the myelin in MS. Here, we hypothesize that transplantation of mouse bone marrow-derived oligodendrocytes (BMDOs) and BMDOs transfected with Ephrin proteins (BMDO+Ephrin), which are known to enhance cell and axonal migratory capacity, may produce therapeutic benefits in animal models of MS.

Gender differences in the immune system activities of sea urchin Paracentrotus lividus

In the immune system of vertebrates, gender-specific differences in individual immune competence are well known. In general, females possess more powerful immune response than males. In invertebrates, the situation is much less clear. For this purpose we have chosen to study the immune response of the two sexes of the echinoderm Paracentrotus lividus in pre- and post-spawning phases. The coelomic fluid from the echinoderms contains several coelomocyte types and molecules involved in innate immune defenses. In this article we report that the degree of immune responses in the P. lividus differs according to sex in both pre- and post-spawning phases. We found in all tests that females were more active than males. The results indicate that females possess a significant higher number of immunocytes consisting of phagocytes and uncolored spherulocytes. Since the immunological activity is mainly based on immunocytes, it was not surprising that females possessed the highest values of cytotoxicity and hemolysis activity and showed a greater ability to uptake neutral red and phagocyte yeasts cells, while the average number of ingested particles per active phagocyte was not significantly different. Furthermore, agglutinating activity was more evident in the coelomocyte lysate and coelomic fluid of females than in those of males. Finally we found that the acidic extract of female gonads possessed greater antimicrobial activity than that of male gonads. These results make it very likely that gender differences in the immune response are not restricted to vertebrates; rather, they are a general evolutionary phenomenon.

Immune protection of Mozambique tilapia (Oreochromis mossambicus) exposed to different infectious doses of ectoparasite (Cryptocaryon irritans)

The objectives of the present study were to standardize a reproducible infection procedure with Cryptocaryon irritans and to examine the effects of infectious dose level on the immune protection in Mozambique tilapia (Oreochromis mossambicus). This study demonstrated that direct enumeration of trophonts on the pectoral fin was useful to quantitatively assess immune protection against C. irritans. The number of trophonts on a pectoral fin was positively correlated with infectious dose of live theronts. Fish immunized by direct exposure under controlled laboratory conditions allowed for in depth examination of the effects of the degree of infectious dose on immune response. There was no significant positive correlation between the initial infectious dose and degree of immune responses. Mozambique tilapia initiated a strong immune protection by direct exposure with even a small number of parasites (e.g. 300 theronts per fish). Moreover, as the result of the protein analysis, we identified 28kD proteins that could be responsible for the immobilizing antigen.

Abstract 2450: Resistance of CD44+ hepatocellular carcinoma cancer stem cellsto immune effector responses

Abstract Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. There is little therapy for advanced disease and recurrence rates can be as high as 50% following resection. Evidence in several tumor types suggests that cancer stem cells (CSCs) contribute to tumorigenicity, therapeutic resistance and recurrence, however the HCC CSC phenotype remains to be completely defined. HCC recurrence is influenced by the degree of immune response in the tumor microenvironment. Therefore, we aimed to characterize HCC-CSCs phenotype and investigate the interaction between CSCs and immune cell subsets. To identify a dominant CSC population in HCC, we examined several putative CSC markers, including CD44, CD90, CD133 and EpCAM on primary human resected HCCs (n=6), HCC xenografts (n=2), and HCC cell lines (n=3) using flow cytometry. Cells from all sources consistently showed discrete populations of CD44+ cells (2-40%), while other common CSC markers showed significant heterogeneity. CD44+ cells isolated from HCC xenografts or HepG2 cells by fluorescence-activated cell sorting (FACS) demonstrated enhanced tumorigenic potential with as little as 100 cells implanted into NOD-SCID/IL-2Rgnull mice compared to no tumor from 100 CD44− cells. CD44+ cells were also able to produce heterogenic tumor mass in vivo. Moreover, CD44+ cells demonstrated increased sphere forming capacity in serum free media (2 fold, p&amp;lt;0.05), and increased resistance to the chemotherapeutic agents cisplatin and doxorubicin in vitro. Additionally, CD44+ HCC cells were resistant to effector cytokines such as IFNγ and TNFα and effector responses during co-culture with anti-CD3/anti-CD28 activated T cells from healthy donor PBMCs. CD44+ HCC cells had 2-fold increased expression of B7-H1, a co-inhibitory molecule for T cells, when compared to non-CSCs during exposure to activated T cells or effector cytokine IFNγ, suggesting a possible mechanism of resistance to immune effectors in the HCC microenvironment. In conclusion, CD44 discriminates for the HCC CSC as evidenced by CD44+ subset demonstrating enhanced tumorigenicity, sphere forming capacity and resistance to chemotherapeutic agents. CD44+ CSC are also resistant to activated T cells and effector cytokines suggesting that microenvironmental factors related to immune response may be important for HCC recurrence or progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2450. doi:10.1158/1538-7445.AM2011-2450

Effect of antigens on colony forming efficiency of stromal clonogenic cells and expression of cytokine genes in primary cultures of bone marrow and spleen of mice

Presence of microbial cells preparation (HCL – extract of group A streptococcus) in primary cell cultures of bone marrow (BMCC) and spleen (SCC) of CBA mice induced the expression mRNA of proinflammatory cytokines genes: IL-2, IL-6 and IL-8 in BMCC; in SCC cultures mRNA IL-1 β and IL-6 appeared and mRNA IL-4 disappeared. Injection of S. typhimurium antigen complex to mice CBA increased 5 times colony forming efficiency (CFE) and, respectively, content of stromal precursor cells (CFU-F) in femur bone marrow and 9 times in spleen of these animals with maximum at the first day. In both primary BMCC and SCC from immunized animals expression of proinflammatory cytokines genes IL-1 β, IL-6, IL-8 and TNF- α was revealed - in BMCC on 1 - 3 day after immunization, and in SCC – up to 15 days. In CBA mice injected with polyvinylpyrrolidone (PVP) CFE and number of CFU-F in BMCC and SCC increased 1, 9 and 1, 8 times only and expression of genes IL-6, IL-8 and TNF- was observed only on the first day. In СВА/N xid mice there was neither increase CFU-F in the corresponding organs, nor expression of proinflammatory cytokines genes in primary cultures. The data suggest the possibility of positive participation of stromal cells in the development on of immune response in organism. Degree of activation of stromal tissue in immunized mice, apparently, correlates with the degree of immune response, supposing a close relationship between stromal tissue and immune system.

Peritransplant Monitoring of Immune Cell Function in Adult Living Donor Liver Transplantation

Purpose We evaluated the clinical utility of peritransplant in vitro assays of immune cell function in adult living donor liver transplant (LDLT) recipients. Methods In particular, we measured immune cell function, using the ImmuKnow assay, in 107 adult LDLT recipients and 200 potential living liver donors (control group) admitted to our center between July 2008 and January 2009. Results In the control group, the mean proportion of T-helper/inducer cells was 36.8% ± 8.2%. The degree of immune response was strong in 12%, moderate in 77%, and low in 11%. In the study group, the degree of immune response within the first month was strong in 4.6%, moderate in 38.2%, and low in 57.2%, thus significantly lower than in the control group ( P < .001). ImmuKnow results and tacrolimus levels did not show a significant correlation ( r 2 = .002, P = .392). Although six patients showed biopsy-proven acute cellular rejection, none showed a strong immune response. Patients with overt infection showed a lower immune response. Conclusions These results indicate that peritransplant assessment of immune response using the ImmuKnow assay does not reliably predict the occurrence of acute rejection. Additional studies are necessary to accurately assess the clinical utility of immune response monitoring.

Cerebral amyloid angiopathy and microhemorrhages after amyloid beta vaccination: case report and brief review

After the interruption of the international multicenter Phase 2 clinical trial with active immunotherapy based on synthetic Abeta42 (AN1792), few reports about the neuropathological findings in those patients and those from the Phase 1 clinical trial were published. These reports described some pathological similarities among the patients such as a reduction in the burden of amyloid plaques, the reactions of microglia/macrophages and the persistence of neurofibrillary tangles and neuropil threads. In addition, a lymphocytic inflammatory infiltrate as well as white matter lesions were present in some cases with meningoencephalitis. In both animal models of vaccination, as well as some vaccinated patient samples, there appears to be a correlation between vaccination and hemorrhages. Subsequently, two series reports concerning 8 patients from the Phase 1 initial trial showed that immunization with Abeta42 seemed to result in clearance of amyloid plaques, but did not prevent progressive neurodegeneration and that it increased vessel wall amyloid angiopathy as well as cortical microhemorrhages. Recent clinical data gave further encouraging results regarding vaccination in humans demonstrating that long term follow-up of patients from the second clinical trial revealed reduced functional decline, at least, in antibody responders. Here we describe a patient diagnosed with Alzheimer's disease who also participated in the Phase 2 clinical trial. A neuropathological examination confirmed Alzheimer's disease without meningoencephalitis and revealed a severe amyloid angiopathy with frequent microhemorrhages, the decrease of amyloid load being difficult to ascertain. Our results are in agreement with previous studies and confirm the presence of severe amyloid angiopathy after vaccination. The latter may be a transient phenomenon depending on the degree of immune response and the pathological stage of the disease when the patient underwent treatment. In addition, our vaccinated case also demonstrated microhemorrhages and microinfarcts which were already noticed to occur with a higher density in immunized Alzheimer's disease patients.

Influence of n-3 polyunsaturated fatty acids (PUFA) on the antigen-presenting function of human monocytes.

N-3 polyunsaturated fatty acid (PUFA)-rich diets are associated with suppression of cell mediated immune responses and there is growing interest in the potential use of dietary fish oil [rich in the n3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid @HA)] supplementation in the treatment of disorders involving an overreactive immune response, such as rheumatoid arthritis [see 1 for review]. Specific immune responses are initiated by the presentation of antigen to helper T-lymphocytes on the surface of an antigen-presenting cell (APC). A pre-requisite for this function of APCs is the cell surface expression of major histocompatibility complex (MHC) class I1 molecules (HLA-DR, -DP and D Q , aided by the presence of adhesion molecules. It has been shown that the percentage of MHC class 11-positive monocytes and the density of these molecules on the cell surface can alter the degree of immune responsiveness of an individual [2]. We have previously shown in vitro that EPA can inhibit the expression of the MHC class I1 molecule HLA-DR and of the adhesion molecule ICAM-1 on both unstimulated monocytes and on interferon-gamma (IFN-g) activated human monocytes [3]. In conaast, DHA increased the expression of these surface molecules on unstimulated monocytes, although it inhibited their expression on IFN-g stimulated cells in a similar manner to EPA [3]. In a dietary study, we observed a reduction in the relative number of HLA-DR and ICAM-1 molecules expressed on human peripheral blood monocytes following 3 weeks of fish oil supplementation [4]. Since most commercially available fish oil supplements contain a mixture of EPA and DHA, we undertook further in virro experiments to determine the combined effect of these n-3 PUFA on the cell surface expression of surface molecules involved in the process of antigen-presentation. In addition, the antigen-presenting function of monocytes, following incubation with or without n-3 PUFA, was assessed using tetanus toxoid as a challenge antigen. Purified monocytes, obtained from healthy volunteers, were incubated with or without a mixture of EPA and DHA (final total concentration 20 pg/ml, combined at the same ratio as is commonly found in fish oil supplement capsules, ie. 2:l) in RPMI culture medium supplemented with 5% fetal calf serum for 48 h at 37'C. In addition, parallel cultures were performed in the presence of IFN-g (400 U/ml) to stimulate upregulation of MHC class I1 molecule expression by the monocytes.

Immune tolerance to Factor VIII: the international registry data.

Among the problems related to the treatment of classic hemophilia, the presence of inhibitors (alloantibodies) to foreign Factor VIII (F.VIII) is one of the most serious. These antibodies may arise at any age, but the cumulative risk of developing an inhibitor one year after the first treatment with a factor concentrate is between 22% and 25%. 1,2The presence of such antibodies can render any further administration of F.VIII ineffective. On the basis of the speed and degree of immune response to F.VIII, patients have been divided into high- and low-responders.3This is an arbitrary classification, but it is related to important treatment characteristics. Low responders, that is patients whose maximum inhibitor titer is <10 Bethesda Units (B.U.), can be treated with F.VIII, albeit at higher doses; however, high-responders can seldom be treated with F.VIII and comprise the so-called “refractory hemophiliacs.”

Antibody prevalence against rubella among hospital personnel in Nigeria: Implications for health care system and immunisation policy

Among 385 sera from Nigerian hospital personnel aged 15–39 years, 289 (75%) had an antibody titer corresponding to immunity against rubella, compared with 346 (90%) of the sera from Swedish women of the same age group. The frequency of high immune level against rubella did not change with age among Nigerians compared with a decrease in immunity with increasing age in the Swedish individuals. This probably is due to the differences between the dynamics of the development of natural immunity and immunity acquired through vaccination. In Nigeria, socio-economic factors were related with the degree of immune responses while sex was not. The results highlight the importance of immunization among hospital personnel and eventual vaccination of the whole population in Nigeria and the continuous surveillance of rubella immunity and periodic re-evaluation of immunization policies.

Effects of Stimulated or Immunologically Activated Macrophages on the Induction of Immune Responses to Listeria monocytogenes

The influences of peritoneal macrophages induced by proteose peptone, Corynebacterium parvum (C. parvum) or Bacillus Calmette Guérin (BCG) on the initiation and development of immune responses and protection against Listeria monocytogenes infection were studied in mice. Mice treated intraperitoneally (i.p.) with proteose peptone 4 days previously showed much the same level of protection against an intraperitoneal infection with Listeria as untreated mice. Mice treated i.p. with C. parvum 4 days previously, of which peritoneal macrophages had increased abilities for intracellular killing of Listeria and 0 - 2 generation as compared with peptone-elicited macrophages, exhibited an enhanced resistance against the listerial infection. The degree of immune responses, as assessed by delayed footpad reaction (DFR), was rather depressed in these mice because C. parvum-activated macrophages acting as scavenger cells reduced the amount of effective antigenic stimulation. BCG-activated peritoneal macrophages from mice treated i.p. with BCG 14 days previously showed a strong ability for antigen presentation in correlation with increases in the number of la-bearing macrophages and in the level of interleukin 1 (IL 1) production. These mice showed an early appearance of DFR response and a markedly enhanced resistance against the listerial infection. These results suggested that the differences in macrophage activities as scavenger cells, cytokine-secreting cells and antigen presenting cells may account for the differences in the responsiveness against listerial infection in peptone-, C. parvum- and BCG-treated mice.

Quantitation of mouse monoclonal antibody and human anti-mouse antibody response in serum of patients.

The assays required to study pharmacokinetics of monoclonal antibodies and human anti-mouse antibody response in man, utilizing enzyme linked immunosorbent assay, have been at best semi-quantitative. We have developed and well characterized a quantitative assay for measurement of murine monoclonal antibodies and human anti-mouse antibody in circulation of patients injected with murine monoclonal antibodies. The sensitivity of mouse IgG assay is approximately 1 ng/ml and cross reactivity of IgG's from other species were less than 0.01%. The pre-therapy samples from 30 patients treated with monoclonal antibody CO17-1A as well as serum from 54 individuals had no detectable human anti-mouse antibody indicating specificity. The sensitivity of this assay was approximately 10 mg/ml. The utility of these assays was demonstrated in a group of patients receiving 400 mg of monoclonal antibody CO17-1A. The half-life and the degree of immune response can be measured using these assays.

Effect of induction of t-cell-dependent antibody with sheep red blood cells on p-450-dependent and -independent xenobiotic metabolizing enzymes

The effect of an antigenic challenge with sheep red blood cells (SRBC) on the activities of cytochrome P-450-dependent and -independent xenobiotic metabolizing enzymes and on lipid peroxidation in the liver was investigated. The studies were carried out using three mouse strains of C57B1/10 and three strains of C3H backgrounds which are cogenic, differing genetically at the H-2 complex. The basal levels of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase (7-Ec) were different among congenic strains. The activity of 7-Ec was lower in C3H background mice than in B10 background mice. Similarly, the difference due to the strain and the H-2 locus was detected in the activities of P-450-independent enzymes such as malathion and diethyl succinate carboxylesterases, glutathione S-transferase, and epoxide hydrolases in microsomal and cytosolic fractions. The degree of immune responsiveness in these mice was determined by a plaque forming cell assay. Within the same background, the H-2 b mouse strain was a high responder and the H-2 k a low responder to SRBC. However, treatment with SRBC had no significant depressive effect on P-450-dependent enzyme activities except in C3H/He. Activity of AHH was suppressed in C3H/He mice. Treatment with SRBC had no effect on P-450-independent enzyme activities except for malathion carboxylesterase: the activity was increased in C3H/He and C3H.JK, whereas it was decreased in B10. The basal level of lipid peroxidation was lower in C3H/He and C3H.JK. The treatment produced a significant enhancement in lipid peroxidation in C3H/He, B10 and B10.BR (P < 0.05) with a concomitant increase in xanthine oxidase activity (P < 0.05). Thus, the present study revealed that a specific antigenic challenge, unlike non-specific immunostimulants (e.g. poly IC, endotoxin), does not necessarily inhibit P-450-dependent xenobiotic metabolizing enzymes even though antigen challenge increased XO activity and lipid peroxidation. The possible roles of an increase in lipid peroxidation and xanthine oxidase activity in immune response to SRBC and xenobiotic metabolizing enzymes are discussed.

RESULTS OF PROPHYLACTIC INOCULATION AGAINST PNEUMOCOCCUS IN 12,519 MEN

1. From a study of the agglutinins and protective power of the serum of 42 persons vaccinated against the pneumococcus, Types I, II, and III, it is demonstrated that a definite immune response has been secured to Types I and II by the dose of vaccine employed. Little evidence of response to Type III can be demonstrated by these methods, but this is of less significance in that in animals it is relatively difficult to secure antibodies against this strain in the serum, even though a considerable degree of active immunity may have been produced in the vaccinated animal. 2. The degree of response to the vaccination appears to be dependent upon the total dosage of each type of pneumococcus administered. While some response may be elicited by 2(1/2) billion cocci of each type, a much more constant and greater response follows 13 billion. 3. In subcutaneous administration the manner in which the total dosage is divided, whether given in a single large dose, in seven small daily doses, or in three to five moderate doses at 3 to 7 day intervals, seems to have little influence upon the degree of immune response, provided the total dosage is the same. 4. The local and general toxic reaction varies greatly in different individuals. The smaller the individual doses, the fewer are the severe reactions. This makes it desirable to divide the total dosage into as many inoculations as circumstances make practicable. 5. At Camp Upton 12,519 men have been vaccinated against Pneumococcus Types I, II, and III. Three or four doses were given at intervals of 5 to 7 days with a total dosage of 6 to 9 billion of Types I and II and 4(1/2) to 6 billion of Type III. 6. During the 10 weeks that have elapsed since the vaccination, no cases of pneumonia of these three types have occurred among the men who had received two or more injections of vaccine. 7. In a control of approximately 20,000 men there were twenty-six cases of Pneumococcus Types I, II, and III pneumonias during the same period. 8. The incidence of Pneumococcus Type IV pneumonia and streptococcus pneumonia was much less among the vaccinated troops than among the unvaccinated. No explanation has been advanced for this difference. 9. Small sterile infiltrations disappearing spontaneously occasionally follow the injection of large doses of pneumococcus vaccine and appear to be an expression of cutaneous hypersusceptibility. 10. The persons who develop these lesions exhibit local reactions to each dose of vaccine. They also give abnormally marked reactions to intradermal injections of pneumotoxin. They do not, however, exhibit anything notable in the agglutinative or protective powers of their sera after vaccination. Whereas the immune response is characteristically specific for the type of pneumococcus, this reaction is not specific for any type. We have found no evidence that Type III is more prone to elicit these severe local reactions than are Types I and II. 11. Prophylactic vaccination against pneumococcus of Types I, II, and III is practical and apparently gives protection against pneumonia produced by these types. It remains to be determined how long this immunity persists.